Uwe Trinks

Modelling study of protein kinase inhibitors: Binding mode of staurosporine and origin of the selectivity of CGP 52411

SummaryA model for the binding mode of the potent protein kinase inhibitor staurosporine is proposed. Using the information provided by the crystal structure of the cyclic-AMP-dependent protein kinase, it is suggested that staurosporine, despite a seemingly unrelated chemical structure, exploits the same key hydrogen-bond interactions as ATP, the cofactor of the protein kinases, in its binding mode. The structure-activity relationships of the inhibitor and a docking analysis give strong support to this protein tyrosine kinase is rationalized on the basis of the model. It is proposed that this selectivity originates in the occupancy, by one of the anilino moieties of the inhibitor, of the region of the enzyme cleft that normally binds the ribose ring of ATP, which appears to possess a marked lipophilic character in this kinase.

Inhibitory activity and selectivity of staurosporine derivatives towards protein kinase C

Abstract The synthesis and in vitro protein kinase C (PKC) inhibition of a series of staurosporine derivatives is described. Essential for activity is a free NH of the lactam portion of the molecule. A large variety of substituents is tolerated at the secondary amine, although in most cases these modifications lead to a decrease in activity. Acylation of the methylamino group leads generally to the most selective derivatives with respect to other serine/threonine and tyrosine kinases.

Synthesis of N-Phenylpyrrole Carboximides

Several N-phenylpyrrole carboximides were synthesised using acyl isocyanates as intermediates.